Peptides and their derivatives are becoming an increasingly important class of pharmaceuticals, both as drugs [Lien, S.; Lowman, H. B. Trends in Biotech. 2003, 21, 556-562.] and as drug delivery vehicles. [Gariepy, J.; Kawamura, K. Trends in Biotech. 2001, 19, 21-28.] Pharmacokinetics, defined as the in vivo absorption, distribution, metabolism, and excretion (ADME) profile of a drug, [Undevia, S. D.; Gomez-Abuin, G.; Ratain, M. J. Nat. Rev. Cancer 2005, 5, 447-458.] can be a factor in determining the efficacy and toxicity of peptide-based pharmaceuticals.
However, conventional peptide chemistry often fail to effectively provide avenues for the tailoring of pharmacokinetic characteristics of peptide-based pharmaceuticals. More specifically, conventional peptide synthesis methods typically fail to effectively provide routes to highly fluorinated β-amino acids. Further, delivery of drugs cross the blood-brain barrier (BBB) can be a very challenging issue. While fluorination has been used to enhance membrane permeability of other types of molecules, conventional peptide-based pharmaceuticals typically fail to effectively employ fluorinated moieties to enhance trans-BBB delivery. Moreover, conventional peptide-based pharmaceutical protocols typically lack effective non-invasive monitoring of drug pharmacokinetics, despite the much wider chemical shift range and much greater sensitivity of 19F magnetic resonance spectroscopy (19F MRS). Thus, despite conventional peptide synthetic methodology, there remains a need for methods and compositions that overcome these deficiencies.
In contrast to conventional methods, the incorporation of fluorinated moieties can alter the pharmacokinetic characteristics, and thus the efficacy and toxicity, of peptide-based pharmaceuticals. Further, incorporation of fluorinated moieties can enhance trans-BBB delivery of peptide-based pharmaceuticals. Moreover, incorporation of fluorinated moieties can also provide functional groups that can serve as reporters of peptide pharmacokinetics via 19F MRS.